Disrupting cellular memory to overcome drug resistance

Gene expression states persist for varying lengths of time at the single-cell level, a phenomenon known as gene expression memory. This study develops a lineage tracing-based technique (scMemorySeq) to quantify memory and identify cells that switch states. Applied to melanoma cells, it quantifies long-lived gene expression fluctuations predictive of therapy resistance and identifies PI3K and TGF-β pathways as state switching modulators. A pretreatment model using PI3K inhibition before targeted therapy reduces resistance. The study presents a method for finding modulators of gene expression memory and their associated cell fates.

Guillaume Harmange, Raúl A. Reyes Hueros, Dylan L. Schaff, Benjamin Emert, Michael Saint-Antoine, Laura C. Kim, Zijian Niu, Shivani Nellore, Mitchell E. Fane, Gretchen M. Alicea, Ashani T. Weeraratna, M. Celeste Simon, Abhyudai Singh, Sydney M. Shaffer